The goal of the application is to examine whether common genetic variation in fatty acid (FA) metabolic pathways is associated with sudden cardiac arrest (SCA) risk in humans. Fatty acid metabolism is complex with multiple determinants of membrane FAs and intracellular FA derivatives, and multiple effects, cell membrane-dependent and membrane independent, that might alter cardiac ion channels and SCA risk. Taking advantage of existing blood specimens and clinical data from several well characterized population- based studies, we propose to investigate the association of common variation in FA metabolic pathways with the risk of SCA. We will examine 92 candidate genes in interrelated pathways that influence circulating FAs, the uptake of FAs by cardiac cells, cardiac energetics and nuclear signaling, and eicosanoid production. Using a case-control study design, we will examine the association of common variation in candidate genes and SCA risk in 2600 European-American SCA cases and 2600 European-American controls;and, we will examine the associations in 450 African-American SCA cases and 900 African-American controls. Blood specimens and clinical data for the SCA cases will come primarily from the Cardiac Arrest Blood Study Repository (CABS-R), where blood samples have been collected since 1988 from patients with SCA attended by paramedics in Seattle and King County (Washington). Control specimens and data will be from two population-based studies of cardiovascular disease conducted in the same county. The collection of new blood specimens in the CABS- R, together with SCA cases from the Cardiovascular Health Study, will allow us to replicate the findings among European Americans with 1000 new cases and 1000 new controls. In addition to examining main effects, we will use the 2600 European-American SCA cases and a case-only design to investigate gene-gene interactions and gene-environment interactions. We also will examine whether common variation in cardiac energetics and eicosanoid pathways modifies the associations of red cell membrane n-3 polyunsaturated FAs and trans-fatty acids with SCA risk. Our focus on human genetic variation in interrelated pathways of FA metabolism that have the potential to influence cardiac ion channel function and SCA risk is novel;although the methods used to address the aims are well-established. The information on genetic susceptibility to SCA risk derived from the proposed research will inform basic, clinical, and population-based research and enhance clinical and public health efforts to reduce mortality from SCA in the community. In short, we combine expertise in cardiovascular and genetic epidemiology, statistical genetics, molecular cardiology, genomics, and fatty acid metabolism with unique resources, DNA and clinical data assembled over the past 18 years from several large populations, to identify novel genetic factors that influence susceptibility to SCA. The proposed study will provide novel information on the association of human genetic variation in FA metabolism and the risk of sudden cardiac arrest, one of the most common mechanisms of mortality due to heart disease in the United States. The identification of genetic susceptibility factors to life-threatening ventricular arrhythmia in human populations will provide insight into the mechanisms of an important and devastating disease, and perhaps identify better targets for prevention. As a result, the proposed research has implications both for the development of new knowledge and the application of knowledge to reduce mortality from sudden cardiac arrest in the community.